Prostaglandins are a group of cyclic fatty acids that possess diverse and potent biologic activities affecting cell function in every organ system. The parent compound, prostanoic acid, contains a 20 carbon chain with a cyclopentane ring. ##STR2## Variations in the number and position of the double bonds and hydroxyl groups determine the physiologic activities of the various prostaglandins.
Conventionally, prostaglandins are divided into types E, F, A, B, C and D based on functions in the cyclopentane ring. Numerical subscripts refer to the number of unsaturations in the side chains. .alpha. or .beta. subscripts refer to the configuration of the substituents in the ring. The naturally occurring prostaglandins are types E, F, A and B. All naturally occurring prostaglandins have a trans.dbd.13,14 position bond and a hydroxyl group at C.sub.15. ##STR3##
Further, the E- and F-types possess an additional hydroxyl at C.sub.11. At C.sub.9, E-type prostaglandins have a carbonyl function while F-type prostaglandins have a hydroxyl. In general, A- and B-type prostaglandins may be regarded as dehydration products of E- and F-type prostaglandins; i.e., the removal of the C.sub.11 hydroxyl and the formation of a double bond in the cyclopentane ring.
The biologic activities of prostaglandins of the E-type include activities as hypotensive agents, antilipodemic agents, bronchodilators, fertility control agents and gastric secretion inhibition agents. Bergstrom, et al., PHARMACOL., REV., 20:1 (1968); see also U.S. Pat. No. 3,069,322 and U.S. Pat. No. 3,598,858. However, E-type prostaglandins generally decompose at room temperature and above, and also in the presence of small amounts of acid or base. Accordingly, E-type prostaglandins are unstable in conventional pharmaceutical formulations. Even in neutral aqueous solution or in a neat state there is a gradual decomposition of E-type prostaglandins to A- and B-type prostaglandins. Stability of the E-type prostaglandins has been observed in some solutions and in solid form at -20.degree. C. or lower. However, storage at such temperatures is impractical and administration to mammals at such temperatures is practically impossible. Some success at stabilization has been reported in: U.S. Pat. No. 3,749,800; U.S. Pat. No. 3,826,823; U.S. Pat. No. 3,829,579; and U.S. Pat. No. 3,851,052; see also Srivastava et al., LIPIDS, 8:592 (1973); where ethyl acetate, chloroform and ethanol are employed as solvents for E-type prostaglandins. Such solvents, however, are unsuitable for pharmaceutical dosage applications without dilution with water, which causes rapid decomposition.
More recently, stability of E-type prostaglandins was reported with use of triethyl citrate as a solvent, U.S. Pat. No. 4,211,793.